Cancer and inflammatory diseases are multifactorial diseases and different mode of therapies are being exploited and attempted. Glioblastomas (GBM) are the most frequent and most malignant form of brain tumors. Tumor angiogenesis, invasiveness and rapid growth go in concert in GBM. The tumor microenvironment exhibits expression of pro-inflammatory molecules that promote migration and invasion of tumor cells. There is increasing evidence of the role of the pro-inflammatory molecules in making glioma and other tumors more aggressive and resistant to chemo- and/or radio-therapy.
Common pathways may promote tumor invasiveness and expression of pro-inflammatory molecules in GBM. Of these COX-2 and cytokines like IL1β, IL6 are the known mediators of both the processes. However the therapeutic translation of this knowledge has been limited. FAT1, a member of the cadherin gene family, is the human homologue of the Drosophila fat. Fat in D. melanogaster is a known tumor suppressor gene acting via the Salvador-Warts-Hippo (SWH) signaling pathway, and is essential for controlling cell proliferation during development and regulating planer cell, and any defect in the expression of fat would lead to tumor development. In Drosophila, fat is an upstream regulator of the SWH pathway. The signaling molecules of SWH pathway are conserved in human but the role of FAT1 as an apical regulator has not yet been established. Disruption of fat causes imaginal disc tumors in Drosophila. The fat gene was first discovered in Drosophila followed by the identification of its orthologue in man, rat, mouse and zebrafish etc.
The expression profile of FAT1 has been studied in human fetal and adult tissues. FAT1 in human is reported to be localized to region of chromosome 4q35. The expression of FAT1 peaks in embryonic stages and diminishes later in adult life. High levels of FAT1 transcripts were found in kidney, lungs, and eye epithelia, and were down regulated in the corresponding adult tissues, indicating the role of FAT1 in organ development. FAT1 is also known to have a role in cell polarity and migration. FAT1 is found to be involved in the glomeruli as a slit junction adhesion molecule and have been found to be interacting with atropine in regulating cell orientation and migration. FAT1 is up-regulated in cell migration, induces cellular process formation when overexpressed, and is necessary for efficient wound healing. FAT1 was found to be localized at filipodial tips, lamellipodial edges, and cell-cell boundaries, overlapping with dynamic actin structures.
Very few reports are available on the role of FAT1 in human cancer. A study from the inventors has shown low expression of and loss of heterozygosity (LOH) at the FAT1 locus in the gliomas. Studies have shown altered expression of FAT1 in different cancers but the exact role of FAT1 has not been fully elucidated, even the mechanism of action of FAT1 in mammalian epithelial cell migration is not fully understood. The signaling cascades and cellular processes through which FAT1 acts in different contexts are still being elucidated and very few functional studies are available on the role of FAT1 in human cancers, including GBM. However the main focus of FAT1 so far in the literature has been as a tumor suppressor gene.
There are studies showing LOH and/or deletion of the chromosome 4q34-35 region in many tumors including gliomas but the FAT1 gene itself has not been analyzed and implicated. LOH/alterations in the chromosomal 4q34-35 region was found in grade IV gliomas using microsatellite markers, Small Cell Lung Carcinoma, hepatocellular carcinoma and cervical carcinoma etc. In all these LOH studies, a significant association of 4q34-q35 region with increased risk of progression to higher grade or with the malignancy of the tumors was suggested. Since the FAT1 gene is located in this region it appears to have an important role to play in the development and progression of these tumors.
A positional cloning strategy, combined with association analysis has provided evidence that FAT1 confers susceptibility to bipolar disorder.
It is important to note that all the previous literature has concentrated on FAT1 as a tumor suppressor gene and there is no literature on FAT1 promoting either tumourigenesis or inflammation or the link between the two.
The signaling cascade(s) being regulated by FAT1 gene and the function of FAT1 gene in human cancers including GBM is not known. Therefore, development of the present invention has helped to uncover the precise role of FAT1 gene in inflammation and tumors, including GBM.
Till now, targeting pro-inflammatory molecules or related pathways as therapeutic strategies to prevent or treat cancers has had a limited success and there is considerable interest in focusing on such molecules. The transmembrane molecule, FAT1 is thus a novel target for therapeutic intervention in cancer and inflammation as well as the link between the two processes.